Project Summary: Traumatic brain injuries (TBIs) constitute a significant and growing percentage of injuries in the veteran population;sequelae of explosions, motor vehicle accidents and falls. TBI is also a major cause of death and disability in the general population of the US, particularly in those under 40. Approximately 2% of the population is living with a chronic TBI-related disability. There are currently no effective protective or restorative therapies available clinically. In several models of CNS trauma, administration of a neurotrophin (e.g. BDNF, NGF) protects tissues acutely and promotes longer term recovery. However, the neurotrophins are poor drugs as they are labile, exhibit poor CNS penetration and may augment cell death and pain pathways. These properties are due to their polypeptide composition and the stimulation of intersecting signalling pathways through the activation of multiple receptors. These problems may be at least partially circumvented through the use of recently discovered small, stable, non-peptidyl drug-like compounds (designated LM11A) that potently promote neuronal survival through selective interactions with the neurotrophin receptor p75NTR, inhibit proNGF-induced death, and promote neural progenitor cell proliferation. p75NTR and proNGF have been implicated in several neurodegenerative processes, including the apoptotic death of oligodendrocytes in the spinal cord and corticospinal tract neurons in the brain following trauma. We hypothesize that the LM11A compounds will inhibit cell death occurring hours to days following a traumatic injury, and further, that effects on neurogenesis and neurite plasticity will improve brain structure and function at times remote (weeks, months) from the injury. In addition, we postulate that these effects will occur in association with the promotion of survival and differentiative signaling (e.g. via AKT, ERK, NF:B pathways) by the compound, and the suppression of death signaling (e.g. via JNK activation). The specific aims of this proposal are to: 1) to examine changes in cell signaling associated with the inhibition of cell death by a p75NTR-directed compound (LM11A-31) in the context of focal brain trauma, 2) to determine the responses of a model of focal brain trauma to LM11A-31 given in an early/delayed fashion, and in the late/chronic phase, and 3) to determine the roles of p75NTR following injury. Towards these aims, a controlled cortical impact (CCI) model of brain trauma in mice will be used to assess the effects of the LM11A-31 on cell survival and signalling, neuro- and gliogenesis, cholinergic neurite density, and 'depressive'(Porsolt Forced Swim Test) and memory (Morris Water Maze) behaviors in animals treated immediately, up to 24 hrs, or beginning 2 weeks following injury. To further examine p75NTR function and compound mechanisms in TBI, cell death, process dystrophy and neurogenesis will be evaluated in p75NTR deficient animals subjected to CCI. These studies will provide information important for the eventual application of these or related compounds to clinical head trauma, and will advance our knowledge of the roles of p75NTR in pathologic states. The overall goal of this research is to advance the application of these neurotrophic compounds to the treatment of brain trauma and other conditions. PUBLIC HEALTH RELEVANCE: Narrative Brain injuries constitute a significant and perhaps growing percentage of injuries in modern combat and the veteran population, due to explosions, motor vehicle accidents and falls. Current acute and chronic therapies, such as control of brain pressure and rehabilitation training, have limited effectiveness, and new pharmacologic and cell-based approaches are needed. This proposal, to test a promising new nerve cell-survival-promoting compound (called LM11A-31) in models of brain trauma addresses this need directly. The proposed experiments will determine whether delayed-early treatment is effective, and whether treatment long after the injury will improve symptoms. In addition, they will provide insight into the question of whether the compound's main effects are due to improving cell survival, increasing regeneration or both. If effective, treatment with compounds of this type could represent an important advance in the development of new therapies for preserving and recovering tissue and function following brain trauma.